Developing new surfactant substitutes requires (1) understanding the roles of the lipids and proteins in native lung surfactant; (2) developing easy to synthesize analogs of the native surfactant proteins; (3) optimizing lipid composition for low surface tension and rapid respreading and adsorption; (4) understanding surfactant inhibition by serum proteins and optimizing surfactant composition to minimize this inhibition. We will use modern biophysical techniques including Langmuir isotherms, fluorescence and Brewster angle optical microscopy, atomic force microscopy, viscometry, and x-ray diffraction to determine the phase behavior and morphology of lung surfactants. Specifically: (1) SP-B eliminates squeeze-out of unsaturated lipids and makes monolayer collapse more reversible. SP-C is more efficient at eliminating squeeze-out, and is less efficient at altering collapse. Is there an optimal ratio of SP-B to SP-C, or are the proteins interchangable? (2) Can we make a better SP-B and/or SP-C? Based on the known amino acid sequences of SP-B and SP-C, we will synthesize a family of homodimer peptides that mimic the characteristics of SP-B and SP-C. (3) Is there an optimal solid phase fraction in surfactant monolayers? Adding palmitic acid (PA) to DPPC influences the fluid to solid phase transitions and helps lower the surface tension. We plan to determine the composition of the solid phase in model surfactants and Survanta. (4) What leads to surfactant inhibition by serum proteins? Blood, plasma and serum proteins, lysolipids, and meconium may compete for interfacial area or might solubilize or degrade constituents of surfactant, thereby impairing monolayer function. We propose to investigate the interaction of model lung surfactant mixtures with human serum albumin to determine the molecular mechanisms of surfactant inhibition. (S) Can we relate monolayer viscosity to monolayer morphology and composition? We have built a magnetic needle viscometer to carry out systematic studies of LS monolayer shear viscoelasticity as a function of: i) protein content; ii) phase state of the monolayer. Concurrently, an existing double-barrier Langmuir trough will be adapted to do dilational viscoelasticity under the same conditions.